Nuclear receptors (NRs) are ligand-activated transcription factors that regulate the expression of target genes by recruiting co-activator or co-repressor complexes [1]. They are highly involved in diverse physiological processes such as metabolism, development, growth, reproduction and immunity [2-5].
Endogenous ligands or synthetic drugs that target NRs have been used to deal with many major and debilitating diseases. However, only a small percentage of NRs have been targeted, and even for these, drugs that act more selectively would provide huge benefits [6, 7]. New drugs capable of modulating orphan NR activities have the potential to control numerous additional disorders such as metabolic syndrome, cancer, inflammation, depression and anxiety.
Peroxisome proliferator-activated receptors (PPARs) are members of the NR superfamily. In humans, three PPAR genes have been characterized: PPARα, PPARδ (also known as PPARβ) and PPARγ. PPARα is highly expressed in metabolic tissues (brown adipose tissue, liver, kidney) but elevated levels are also present in the digestive (jejunum, ileum, colon, gall bladder) and cardiopulmonary (aorta, heart) systems. PPARα dysfunction is associated with susceptibility to hyperapobetalipoproteinemia, as well as a variety of cardiovascular (myocardial infarction, ischemic heart disease, atherosclerosis, hypertension), immune (psoriasis), metabolic (e.g.: plasma lipid levels, type II diabetes, body mass, plasma triglycerides and cholesterol, liver steatosis and steatohepatitis, hyperlipidemia, obesity, arterial blood pressure) and neurological (Alzheimer's disease) conditions.
PPARδ/β is ubiquitously expressed, and malfunction is most strongly associated with diseases such as colorectal cancer, atherosclerosis, hyperlipidemia, coronary heart disease, type II diabetes, obesity and Alzheimer's [8]. PPARγ is expressed at low levels in most physiology regulating tissues, including the central nervous system (CNS), gastrointestinal system, reproductive system, cardiopulmonary system and metabolic tissues, but is most highly expressed in brown and white adipose tissue. PPARγ dysfunction is associated with susceptibility to glioblastoma, familial partial lipodystrophy, atherosclerosis, hypertriglyceridemia, myocardial infarct, severe obesity, essential hypertension, type II diabetes, diabetic nephropathy, colon cancer, bladder cancer, breast cancer, lung cancer, non-Hodgkin's lymphoma, prostate cancer and skin cancer [9-13]. Associations with Alzheimer's disease, psoriasis and preterm delivery have also been observed [14].
PPARs belong to the “adopted orphan” subgroup of receptors. Although the identities of functionally relevant endogenous ligands have been determined, their physiological relevance is still somewhat controversial. The strongest case for PPARγ endogenous ligands include the lipoxygenase products 13-HODE and 15-HETE, the prostaglandins 15d-PGJ2 (15-deoxy-Δ-prostaglandin J2) and 15-keto-prostaglandin E2-as well as lysophosphatidic acid (1-acyl-2-hydroxy-sn-glycero-3-phosphate, LPA) [15-19], and for PPARα the phospholipid 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (POPhtCho) and leukotriene B4 (LTB4) [20, 21].
In terms of PPAR-directed drugs and associated disease indications, PPARα agonists, such as fibrates, have proven to be highly effective in the treatment of lipid disorders, such as hyperlipidemia and dyslipidemia. For PPARγ, the best known drugs are the thiazolidinediones (TZDs), such as rosiglitazone (Avandia) and pioglitazone (Actos), which are used to treat Type II diabetes and other metabolic syndrome disorders. The latter have become the most deadly and costly diseases of today, and continue to escalate.
TZDs are also being used and tested for a number of other PPARγ related diseases, including Alzheimer's, cancer, preterm delivery [9-11, 22, 23], polycystic ovary syndrome (PCOS) [24], non-alcoholic steatohepatitis [25, 26], psoriasis [27] and autism [28]. However, despite their usefulness and potential, it has become increasingly clear that TZDs produce a number of serious side effects, some of which can prove lethal. These include weight gain, bone loss, hypertension, cardiac hypertrophy and cardiac arrest [29-31]. Recently though, it has been shown that PPARγ ligands that have partial or no agonist activity can still restore insulin sensitivity at similar levels as full agonists without the associated side effects [32].
PPARα is the main target of fibrate drugs, a class of amphipathic carboxylic acids (e.g. clofibrate, gemfibrozil, bezafibrate, and fenofibrate). Fibrates have a good safety profile in humans, increasing high-density lipoprotein (HDL) levels while decreasing triglyceride levels. However, nausea, stomach upset, and sometimes diarrhea have been reported and longtime usage over several years can cause gallstone formation.
Quinones are a class of compounds that can exist in the oxidized (I), semi-reduced (II) or reduced (III) states (FIG. 1B). The quinoid ring system, consisting of a fully conjugated cyclic dione structure [33] is the basic component of this large and important organic compound family. Quinones are involved in many cellular processes and are found in fungi, plants, animals and bacteria [33]. Quinones also share three additional properties; they are colored, strong anti-oxidants and electrophiles [33]. In humans, the prevalent form is CoQ10, which is primarily found in peroxisomes and mitochondria. In peroxisomes, it is assumed to function primarily as a reducing agent of reactive oxygen species produced by metabolism. In the mitochondria, it is a component of complex II of the ATP-producing electron transport chain.
Idebenone is a synthetic analogue of CoQ10 ([34]; compound of Formula I) initially developed by Takeda Chemical Industries, Ltd. (described in the specification for Japanese Patent Examined Publication No. 3134/1987) for the treatment of Alzheimer's disease and other cognitive diseases that might be associated with oxidative damage. Notably, it's relatively short ten-carbon alkyl tail with a terminal hydroxyl group makes it more soluble than CoQ10. Like CoQ10, however, it is a strong antioxidant, and has been shown to inhibit lipid peroxidation and to protect cell membranes and mitochondria from oxidative damage. Idebenone has also been shown to restore mitochondrial electron transport chain function and ATP formation when CoQ10 or other complex II components are missing or inactive. Additional described activities include the inhibition of neuronal Ca2+ channels [35] and anti-inflammatory properties that stem, at least in part, from the inhibition of prostaglandin synthesis [36].
Large clinical trials have shown that idebenone is safe and well tolerated in human subjects [37, 38]. The excellent safety profile of idebenone, and its mitochondrial and anti-oxidant activities, have more recently led to the investigation of its suitability for the treatment of diseases such as Friedrichs Ataxia, Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-Like Syndrome (MELAS), Duchenne Muscular Dystrophy and most recently Leber's Hereditary Optic Neuropathy (LHON) [38-41].